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Be aware that significant debate in the literature persists, and researchers using similar data came to essentially the opposite conclusion.

The "bad luck" hypothesis of cancer etiology did not hold up in an analysis suggesting that at least 70% of cancer risk cannot be explained by intrinsic, tissue-specific factors.

Employing four strategies to assess cancer risk, investigators concluded that random genetic mutations account for no more than 10% to 30% of cancer risk. The remaining risk involves extrinsic factors, including certain biological contributors such as inflammation, as well as environmental insults.

Although mutations cause cancer, the factors leading to the mutations often are not random but involve potentially modifiable factors, Yusuf Hannun, MD, of Stony Brook University Cancer Center in New York, and co-authors argued in an article published online in Nature.

"By applying four distinct [analytic] approaches, we find that the range for the contribution of extrinsic factors is between 70% and 90%," Hannun told MedPage Today. "The extrinsic factors include exposure to carcinogens, exposure to radiation and UV light, papillomavirus, which means there is a need to investigate more to determine what the external factors and how to prevent the effects of these factors on cancer risk and pathogenesis."

The analysis and resulting conclusions counter the findings and conclusions of a study published earlier this year in Science, suggesting that two-thirds or more of the variability in cancer risk can be attributed to the number of stem-cell divisions, or more simply, "bad luck."

Contacted by MedPage Today, the first author of that article stood by its analysis, results, and conclusion.

"Our focus was on relative risk of one tumor compared with the risk of another one. We were interested in relative variations and we found a striking correlation between lifetime risk of cancer and number of stem-cell mutations," said Cristian Tomasetti, PhD, of Johns Hopkins University in Baltimore.

"They are not suggesting any plausible alternative explanation for the correlation that we found. They are not commenting on the correlation," he said of the article by Hannum and co-authors. "They are attempting to use our data and analyses to the relative role of extrinsic factors in cancer and look at the absolute risk. Their question is different."

The analysis by Tomasetti and co-author Bert Vogelstein, MD, also of Johns Hopkins, showed a strong correlation (0.81) between tissue-specific cancer risk and the cumulative number of cell divisions by tissue-specific stem cells. Whether such a correlation "implies a very high unavoidable risk for many cancers" remains controversial, Hannun and co-authors said. However, arguments against the "bad luck" hypothesis failed to offer alternative strategies (to those used by Tomasetti and Vogelstein) to quantify the contribution of extrinsic risk factors in cancer.

For their analysis Tomasetti and Vogelstein performed a literature search and identified 31 tissue types for which quantitative stem cell assessments had been performed. They then plotted the total number of stem-cell divisions during an average human lifetime against the lifetime risk in the U.S. for all of the cancers included in the analysis, resulting in the correlation of 0.81.

"A linear correlation of 0.804 suggests that 65% of the differences in cancer risk among different tissues can be explained by the total number of stem-cell divisions in those tissues," Tomasetti and Vogelstein wrote.

Across the different tumor types included in the analysis, extrinsic, or environmental, factors accounted for 10% to 30% of the risk.

Hannun and co-authors examined the same data, using four different approaches, including data-driven and modeling approaches -- and came back with a diametrically opposite conclusion, at least superficially

First, they reexamined the quantitative relationship between observed lifetime risk for a specific type of cancer and normal stem-cell division, as reported in the Science article. If intrinsic risk factors predominate, similar frequencies of stem cell division would result in similar lifetime observed risk of a cancer.

In fact, they found that such patterns were rare. Their calculations suggested that intrinsic factors accounted for about 10% of risk in most of the cancers.

Hannun and co-authors also mathematically and analytically reviewed recent studies of mutational signatures ("fingerprints") in cancer. They identified 30 distinct signatures and categorized each fingerprint as resulting from intrinsic or extrinsic factors. Intrinsic mutations accounted for a majority of risk in a few cancers, but a majority of the cancers analyzed -- including several common types, such as colorectal and lung -- had a predomination of mutations with links to extrinsic factors.

The third approach made use of epidemiologic data from NCI's Surveillance, Epidemiology, and End Results program. Some cancers had relatively stable incidences over time. However, Hannun and colleagues found that rates for many types of cancer have increased steadily over the past years, resulting in substantially higher rates as compared with baseline values. The observation argues that extrinsic factors are major contributors to the risk of these cancers.

The epidemiologic data showed extrinsic factors account for the majority of risk for all but one of 19 different types of cancer included in the analysis. The lone exception was testicular cancer, for which extrinsic factors were estimated to account for about 45% of the risk.

Finally, Hannun and colleagues performed computer modeling studies of known gene mutations in cancer (intrinsic factors) to derive estimates of the likelihood that a mutation arises from intrinsic processes. They found that when three or more mutations are involved in cancer onset (which they characterized as an accepted parameter), intrinsic factors are insufficient to explain observed risk across cancer types -- thus suggesting only a modest contribution from intrinsic factors. The analysis suggested that extrinsic mutational signatures explained >50% of the risk for 23 of 30 cancers.

Debate Will Continue

Taken together, the two studies help inform discussion about the contributions of both intrinsic and extrinsic factors in cancer etiology, said Graham Colditz, MD, DrPH, of Washington University in St. Louis.

"The first paper didn't ignore [evidence of extrinsic factors] but the interpretation in media coverage and subsequent discussion made it seem as if the reality was ignored," Colditz told MedPage Today. "The new paper actually goes back to migrant studies and to all of the evidence indicating that there are lots of cancers that are very heavily influenced by these extrinsic factors.

"Putting the two studies together does get us closer to understanding that there is likely some variation across organ sites in the underlying risk from cell division and intrinsic risk factors but that for many cancers, the majority of risk is really driven by extrinsic, modifiable factors."

The evidence is far from cut and dried, according to Steve Frank, PhD, of the University of California Irvine. He offered a couple of examples to emphasize the point.

"The amount of cell division explains some of the variance," Frank said in an email. "It is hard to say exactly how much. Other factors are important, for example, the small intestine has about the same amount of cell division as the large intestine, yet small intestine cancers are rare and large intestine cancers are common. This is very well known already.

"It is also clear that if one considers relatively carcinogen-free environments, then intrinsic factors dominant, and if one considers carcinogenic exposures, then extrinsic factors dominate. The data currently do not allow a clear estimate of intrinsic versus extrinsic risk, averaged over all different tissue types and over all different environments."

Hannun and co-authors disclosed no relevant relationships with industry.